Metformin-loaded Chitosan nanoparticles alleviate insulin resistance in the polycystic ovarian syndrome rat model through modulation of PI3K/AKT/ GLUT4 in ovarian tissue

Polycystic ovary syndrome (PCOS) is a common disorder in females characterized by insulin resistance (IR), hyperandrogenemia and anovulation. The etiology of PCOS is unknown. However, disrupted phosphatidylinositol 3-kinase (PI3K) and protein kinase B/AKT signaling pathway may be a possible cause of IR in PCOS. Metformin can activate AKT via PI3K and improve IR. However, metformin alone has shown conflicting results. Chitosan nanoparticles (CSNPs) are natural nano-carriers with anti-diabetic effects. Therefore, we aimed to elucidate the therapeutic potential of metformin-loaded CSNPs (CSNPs-Met) in a letrozole-induced PCOS rat model. The study comprised five groups of rats: control, PCOS, PCOS plus metformin, PCOS plus CSNPs, and PCOS plus CSNPs-Met. Letrozole was found to successfully induce PCOS, as evidenced by elevated serum testosterone levels, homeostasis model assessment-insulin resistance (HOMA-IR), an increased number of cystic follicles, fewer corpora lutea and a disturbed estrus cycle. The pAKT and GLUT4 protein levels were significantly lower in ovarian and muscular tissues than in control group (P < 0.001), suggesting impaired insulin signaling and glucose transport that may contribute to both the metabolic and reproductive disturbances. CSNP-Met showed a significant decrease in testosterone, HOMA-IR, cystic follicles with an increase in the number of corpora lutea, as well as the levels of pAKT and GLUT4 in ovarian and muscular tissues (P < 0.001). In addition, the estrus cycle was restored to normal levels. Hence, CSNPs-Met showed superior efficacy in ameliorating PCOS-associated parameters relative to metformin alone. In addition, these results support future translational studies to explore the clinical applicability of CSNPs in PCOS management.